The Design Rationale

In the design of boronic acid based sensory systems it has been established that two receptor units are required if selectivity is to be achieved for specific saccharides. It has been demonstrated that the A-methyl-D-(aminomethyl)phe-nylboronic acid fragment is particularly effective at signalling these binding events via PET when correctly positioned alongside a suitable fluorophore.  

In designing a range of modular sensors from which quantitative trends are to be derived, a generic scaffold must be established at the start of the project and adhered to throughout, if a meaningful comparison is to be obtained across the series. 

While sensors developed around the anthracene core unit e.g. 80), they have proved to be selective for saccharides such as o-glucose, the rigid core unit (functioning as the scaffold, linker and fluorophore) limits the modifications that can be made to any one part of the system without influencing the sensor as a whole. Perusing the literature it appears that this limitation holds for a great many sensors. 

In adopting a modular approach it was deemed important to design a system in which the receptor, linker and fluorophore units could be connected to the molecular scaffold in such a way as to permit these sub-units to be varied independently. 

Appleton and Gibson investigated the effect of longer linker units between the two receptor units in this system. 1,6-diaminohexane, 1,7-diaminoheptane, 1,8-diaminooctane, 1,12-diaminododecane and 4,4 -diamino 

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Figure 20 Representation of the design rationale for two novel, bone-targeting pTyr mimics, Dmp and Dpp, relative to an x-ray structure [16] of citrate complexed with Src SH2.

Our group is currently developing TAN-67 (Toray), another lead opioid agonist with a characteristic 4a-aryl-decahydroisoquinoline structure. We previously discussed the design rationale and pharmacology of this compound [20, 21]. 

Nalfurafine hydrochloride is a first-in-class, nonaddictive opioid drug that is used as an antipruritic for severe itching associated with hemodialysis. This drug was launched in Japan in 2009. It has a unique morphinan structure that is rarely observed in typical and traditional opioid k agonists. The design rationale for this characteristic compound was described in a previous study [7, 28], and would be of interest to researchers in the opioid field. We will summarize the rationale in Sect. 4. 

Design processes and their results are not sufficiently well documented. This lack of documentation prevents tracing (i) of ideas which have not been pursued further for one or the other reason, (ii) of all the alternatives studied, (iii) of the decision making processes, and (iv) of the design rationale. 

The coordination of PyPs to metal fragments can be performed using them either as free-bases (i.e. with no metal inserted in the internal core) or as metallated units. Alternatively, inner metal centers can be introduced in a second step, after external coordination, depending on the design rationale. The presence of one or more metalloporphyrin imits in the final assembly, in addition to introducing novel reactive functionalities (i.e. the inner metal ions), can vary dramatically its photophysical properties. 

The vertical intent dimension has seven levels. Each level represents a different model of the system from a different perspective and supports a different type of reasoning about it. Refinement and decomposition occurs within each level of the specification, rather than between levels. Each level provides information not just about what and how, but why, that is, the design rationale and reasons behind the design decisions, including safety considerations. 

The links not only provide traceability from requirements to implementation and vice versa to assist in review activities, but they also embed the design rationale information into the specification. If changes need to be made to the system, it is easy to follow the links and determine why and how particular design decisions were made. 

Racemic-HPC, a strong inhibitor of CPT, [28] binds 9-fold better than palmitoyl-carnitine. The chiral material promises to be even better. HAC competes for the carnitine site in the short-chain, but not the long-chain transferase. In summary, the success of these inhibitors attests to the design rationale that the g conformation... 

Together, the partners capture, share, and review all aspects of the design rationale and modify it where necessary. 

For space reasons we do not present the entire models resulting from the design rationale activity. A more complete one can be found in [25] this section the modelling process itself but we describe the output of the process. Task models and scenarios... 

Acyclic derivatives based upon the DTP A ligand core have been reported by Nagano and utilised for targeting and imaging intracellular zinc [22]. The design rationale for such a... 

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